SK6822000A3 - Obsahom a medziprodukty method for the preparation of citalopram, pharmaceutical composition containing the same and intermediates - Google Patents

Abstract

A method for the preparation of citalopram is described comprising reaction of a compound of Formula (IV) wherein R<1> is H or C1-6alkylcarbonyl successively with a Grignard reagent of 4-halogen-fluorophenyl and a Grignard reagent of 3-halogen-N,N-dimethylpropylamine, effecting ring closure of the resulting compound of Formula (VI) and converting the resulting 1,3-dihydroisobenzofuran compound to the corresponding 5-cyano derivative, i.e. citalopram.

Description

A process for the manufacture of citalopram, a pharmaceutical composition thereof and intermediates

Technical field

The present invention relates to a process for the manufacture of the well known antidepressant drug citalopram and to the intermediates used in this process.

BACKGROUND OF THE INVENTION

Citalopram is a well known antidepressant drug, known for several years and has the following formula

(I)

It is a selective, centrally active serotonin reuptake inhibitor (5-hydroxytryptamine; 5-HT), which also has antidepressant effects. The antidepressant effect of the compound has been described in several publications, e.g. J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and by A. Gravem, Acta Psychiatr. Scand. 1987, 75, 478-486. Furthermore, in EP-A 474580 the compound has been reported to be effective in the treatment of dementia and cerebrovascular disorders.

Citalopram was first disclosed in DE 2,657,271 corresponding to US patent 4,136,193. This patent describes a process for producing citalopram and outlines another method that can be used in the manufacture of citalopram.

In the production method described, the corresponding 1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran-carbonitrile is reacted with 3- (N, N-dimethylamino) propyl chloride in the presence of methylsulfinylmethide as a condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with copper (I) cyanide.

In the sketched process, which outlines only in general terms, citalopram can be obtained by cyclizing the compound

ch ₃

I ₃ (II) in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cuprous cyanide. The starting material of formula II is obtained from 5-bromophthalide by two consecutive Grignard reactions, i.e. with 4-fluorophenylmagnesium chloride and subsequently with N, N-dimethylaminopropylmagnesium chloride.

A novel and surprising method of manufacture and an intermediate for the production of citalopram has been described in US Pat. 4,650,884, wherein the intermediate of formula III

(III) is subjected to cyclization by dehydration with strong sulfuric acid to form citalopram. The intermediate of formula III was prepared from 5-cyanophthalide by two consecutive Grignard reactions, i. j. with 4-fluorophenylmagnesium halide followed by N, N-dimethylaminopropylmagnesium halide.

Methods for making the individual enantiomers of citalopram are described in U.S. Pat. No. 4,943,590, from which it is clear that the cyclization of the intermediate of formula III can be carried out under basic conditions.

It has now surprisingly been found that citalopram can be produced in a convenient and safe manner using preferred starting materials. SUMMARY OF THE INVENTION

The present invention provides a process for the manufacture of citalopram comprising the steps of:

a) reacting a compound of formula IV

(IV) wherein R ¹ is H or C _1-6 alkylcarbonyl, with a Grignard reagent of 4-halo-fluorophenyl,

b) reacting the resulting compound of formula V

H

(V) wherein R ¹ is as defined above, with a Grignard reagent of 3-halo- N, N -dimethylpropylamine,

c) cyclizing the compound of formula VI

wherein R ¹ is as defined above, and

d) converting the resulting compound of formula VII

HC _{CH3 CH3} (VII) wherein R ¹ is as defined above, to the corresponding 5-cyano derivative, i.e. citalopram, which is isolated as the base or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides intermediates of formula V.

In another aspect, the invention provides intermediates of formula VI.

In another aspect, the invention provides intermediates of formula VII.

In yet another aspect, the present invention relates to a pharmaceutical composition having an antidepressant effect comprising citalopram produced by the method of the invention.

In the specification and claims, C 1-4 alkyl means a branched or unbranched alkyl group having one to six carbon atoms, such as

For example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.

The Grignard reagents of 4-halofluorophenyl which may be used in step a) are magnesium halides such as chloride, bromide or iodide. Preferably, magnesium bromide is used. The Grignard reagents of 3-halo-N, N-dimethylpropylamine which may be used are magnesium halides such as chloride, bromide or iodide, preferably magnesium bromide. These two reactions are preferably carried out subsequently without isolation of the intermediate.

The cyclization of a compound of formula VI is carried out with an acid or when R ¹ is C 1-4 alkylcarbonyl, it may be carried out via an unstable ester with a base. The acid cyclization is performed with an inorganic acid such as sulfuric or phosphoric acid or an organic acid such as methylsulfonic, p-toluenesulfonic or trifluoroacetic acid. Base cyclization is performed through an unstable ester such as methanesulfonyl, p-toluenesulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl ester with a base addition such as triethylamine, dimethylaniline or pyridine. The basic reaction is carried out in an inert solvent, preferably with cooling, preferably at about 0 ° C, and is preferably carried out in a one-pot manner, ie by esterification and simultaneous base addition.

When R ¹ is H, the conversion of the R ¹ -NH group to a cyano group is preferably accomplished by diazotization followed by reaction with CN '. Most preferably, NaNO ₂ and CuCN and / or NaCN are used. When R ¹ is C 1-6 alkylcarbonyl, it is initially subjected to hydrolysis to give the corresponding compound wherein R ¹ is H and then converted as described above. The hydrolysis can be carried out in an acidic or basic environment.

The process of the invention may be carried out with or without isolation of the intermediates.

The process of the invention can be used to produce the active (S) enantiomer of citalopram. In this case, the compound of formula VI is resolved into the optically active enantiomers in a manner analogous to that described in US patent 4,943,590 to give the (S) -enantiomer of the compound of general formula

-6 of Formula VI, which is used in cyclization step c). Thus, the individual enantiomers of the intermediates of formulas VI and VII, respectively, are encompassed by the formulas.

Other reaction conditions, solvents, etc. are conventional conditions for such reactions and can be readily determined by those skilled in the art.

Starting materials of formula IV wherein R ¹ is H are commercially available or can be prepared by known methods (Tirouflet, J., Bull. Soc. Sci. Bretagne 26, 1959, 35) and compounds wherein R ¹ is acyl may be prepared. from amino compounds (R ¹ is H) by conventional alkylation.

In another embodiment of the invention, R ¹ is C 1-6 alkylcarbonyl, in particular methyl, ethyl, propyl or butylcarbonyl.

In another embodiment of the invention, R ¹ is H.

The compound of formula (I) may be used as the free base or as a pharmacologically acceptable acid addition salt thereof. As acid addition salts, salts formed with organic or inorganic acids may be used. Examples of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bs-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartar, salicylic, citric, gluconic, lactic, cinnamon, apple, apple, apple , aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, such as 8-halo-thiophylins, for example 8-bromothiophylline. Examples of inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The acid addition salts of these compounds can be prepared by methods known in the art. The base is reacted either with a calculated amount of acid in a water miscible solvent such as acetone or ethanol, followed by isolation of the salt by concentration and cooling, or with an excess of acid in a water miscible solvent such as ethyl ether, ethyl acetate or dichloromethane with a spontaneous salt. with relaxing.

The pharmaceutical composition of the invention may be administered by any suitable route and in any suitable form, for example orally in the form of tablets,

-7 capsules, powders or syrups, or parenterally in the form of a conventional sterile injectable solution.

The pharmaceutical composition of the invention may be prepared by methods conventional in the art. For example, tablets may be prepared by mixing the active ingredient with a conventional adjuvant and / or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or solvents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Other adjuvants or additional colorants, flavorings, preservatives, etc. may be used provided that they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the active ingredients and optional ingredients in a portion of the solvent for injection, preferably sterile water, bringing the solution to the desired volume, sterilizing the solution and filling it in suitable ampoules or vials. Any desired additive conventionally used in the art, for example, tonicity agents, preservatives, antioxidants, and the like can be added.

The process of the invention is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4-Dimethylamino-1- (4-amino-2-hydroxymethylphenyl) -1- (4-fluorophenyl) butan-1-ol

A solution of 4-fluorophenylmagnesium bromide prepared from 4-fluorobromobenzene (116 g, 0.66 mol) and magnesium sawdust (20 g, 0.8 mol) in dry THF (500 mL) was added dropwise to a suspension of 5-aminophthalide (30 g). , 0.2 mol) in dry THF (500 mL). The temperature is kept below 5 ° C. When the addition is complete, the reaction mixture is stirred at room temperature for 0.5 h.

A second Grignard solution, prepared from 3-dimethylaminopropyl chloride (25 g, 0.2 mol) and magnesium sawdust (6 g, 0.25 mol) in dry THF (150 mL) was added to the reaction mixture. The temperature is kept below 5 ° C during the addition. The reaction

The mixture was stirred for 0.5 hour, then stirring was stopped and the reaction was allowed to stand overnight at room temperature.

The reaction mixture was quenched with ice water (1000 mL) and acetic acid (60 mL)

g). THF was evaporated in vacuo. The aqueous phase was washed with ethyl acetate (2 x 200 mL). NH 4 OH was added to the aqueous phase to adjust the pH to 9. The aqueous phase was extracted with ethyl acetate (2 x 200 mL) and the organic phase was filtered and washed with water (100 mL). Evaporation of the solvents in vacuo gave the title compound (38.8 g, 58%) as an oil.

¹ H NMR (CDCl 3, 500 MHz): 1.45-1.55 (1H, m), 1.65-1.75 (1H, m), 2.2 (6H, s), 2.27 (1H , m), 2.33 (2H, m), 2.43 (1H, m), 3.6 to 3.7 (2H, _NH2), 3.97 (1H, d, J = 12.5 Hz 4.25 (1H, J = 12.5Hz), 6.58 (1H, d, J = 8Hz), 6.62 (1H, s), 6.62 (1H, s), 6 95 (2H, T, J = 8.5Hz), 7.25 (1H, d, J = 8Hz), 7.45 (2H, dt, J = 1.2Hz, J = 8.5Hz ).

5-Amino-1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran

The crude 4-dimethylamino-1- (4-amino-2-hydroxymethylphenyl) -1- (4-fluorophenyl) -butan-1-ol was dissolved in H 3 PO 4 (60%, 140 g) and heated at 80 ° C for 2 hours. The reaction mixture was then poured onto ice water (1000 mL). NH 4 OH was added to adjust the pH to 9. The aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic phases were filtered, washed with water (100 mL) and dried (MgSO ₄ , 10 g). The solvent was evaporated in vacuo. The title compound is obtained as an oil.

¹ H NMR (CDCl 3, 250 MHz): 1.3-1.5 (2H, m), 2.05-2.3 (1H, s + m), 3.6-3.7 (2H, NH) ₂ ), 5.0 (1H, s), 6.45 (1H, d, J = 1.8Hz), 6.55 (1H, dd, J = 8Hz, J = 1.8Hz), 6 95 (2H, t, J = 8.5Hz), 7.05 (1H, d, J = 8Hz), 7.45 (2H, dt, J = 1.2Hz, J = 8.5Hz) Hz).

1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile

5-Amino-1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran was dissolved in water (100 mL) and H ₂ SO ₄ (8 mL). NaNO ₂ (4.1 g, 0.06 mol) was dissolved in water (20 mL) and added dropwise to the reaction mixture below 5 ° C. The diazotized solution was stirred at 0-5 ° C for 0.5 h. The pH is adjusted to 6.5 by addition of saturated Na ₂ CO _{3 solution} . This solution was added to a mixture of water (100 mL) and toluene (120 mL) containing CuCN (6 g, 0.067 mol) and NaCN (10 g,

-90.2 mol) at 50 to 60 ° C. Stirring is continued for 0.5 hours. The phases are separated and the aqueous phase is then extracted with toluene (100 mL). The combined organic phases were washed with NaCN (1% aqueous solution, 2 x 50 mL). The solvent was removed in vacuo and the residue was chromatographed on silica gel (ethyl acetate: n-heptane: triethylamine, 8.5: 10: 5) to give the title compound (6 g, 32%) as an oil.

¹ H NMR (CDCl ₃ , 250 MHz): 1.35 (1H, m), 1.45 (1H, m), 2.1 (6H, s), 2.15-2.25 (4H,

m), 5.12 (1H, d, J = 12.5 Hz), 5.18 (1H, d, J = 12.5 Hz), 7.00 (2H, t, J = 8.5 Hz) 7.4 (2H, t, J = 8.5Hz), 7.45 (1H, d, J = 7.5Hz), 7.5 (1H, s), 7.58 (1H, d, J = 7.5Hz).

Example 2

4-Dimethylamino-1- (4-acetylamino-2-hydroxymethylphenyl) -1- (4-fluorophenyl) butan-1-ol

A solution of 4-fluorophenylmagnesium bromide, prepared from 4-fluorobromobenzene (11.6 g, 0.67 mol) and magnesium sawdust (2 g, 0.08 mol) in dry THF (50 mL) was added dropwise to a suspension of 5-acetylaminophthalide ( 5 g, 0.03 mol) in dry THF (50 mL). The temperature is kept below 5 ° C. When the addition is complete, the reaction mixture is stirred at room temperature for 0.5 h.

A second Grignard solution prepared from 3-dimethylaminopropyl chloride (3.7 g, 0.03 mol) and magnesium sawdust (0.87 g, 0.036 mol) in dry THF (15 mL) was added to the reaction mixture. The temperature is kept below 5 ° C during the addition. The reaction mixture was stirred for 0.5 hour, then stirring was stopped and the reaction mixture was allowed to stand overnight at room temperature.

The reaction mixture was quenched with ice water (100 mL) and acetic acid (6 g). THF was evaporated in vacuo. The aqueous phase was washed with ethyl acetate (2 x 50 mL). NH 4 OH was added to the aqueous phase to adjust the pH to 9. The aqueous phase was extracted with ethyl acetate (2 x 50 mL) and the organic phase was filtered and washed with water (50 mL). Evaporation of the solvents in vacuo gave the title compound (6.6 g, 63%) as an oil.

¹ H NMR (DMSO-d 6, 500 MHz): 1.15-1.22 (1H, m), 1.40-1.50 (1H, m), 2.02 (9H, s + s), 2 0.5 (1H, m), 2.13 (2H, m), 2.20 (1H, m), 3.95 (1H, d, J = 12.5 Hz), 4.48 (1H, d, J = 12.5 Hz), 7.05 (2H, t, J = 8.5 Hz), 7.14 (2H, dd, J = 8.5 Hz, J = 1.2 Hz), 7.47 (1H, d, J = 8Hz), 7.58 (1H, s), 7.64 (1H, d, J = 8.5Hz).

Claims (17)

PATENT CLAIMS A process for the production of citalopram, comprising the steps of: a) reacting a compound of formula IV (IV) wherein R ¹ is H or C 1-6 alkylcarbonyl, with a Grignard reagent of 4-halofluorophenyl, b) reacting the resulting compound of formula V (V) wherein R ¹ is as defined above with a Grignard reagent of 3-halo- N, N -dimethylpropylamine, c) cyclizing the compound of formula VI ch ₃ IN _x CH ₃ (VI) Wherein R ¹ is as defined above, and d) converting the resulting compound of formula VII between ₃ and ³ hL CH ₃ (VII) wherein R ¹ is as defined above, to the corresponding 5-cyano derivative, ie citalopram, which is isolated as a base or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein R ¹ is H. A process according to claim 1 wherein R ¹ is C 1-6 alkylcarbonyl. The process according to claim 3, wherein C 1-6 alkyl is methyl, ethyl, propyl or butyl. Method according to claims 1 to 4, characterized in that the Grignard reagent used is a magnesium halide, preferably chloride, bromide or iodide. The process according to claim 5, characterized in that the Grignard reagent used in step a) is magnesium bromide. The process according to claim 5, characterized in that the Grignard reagent used in step b) is magnesium chloride. Process according to claims 1 to 7, characterized in that the cyclization of the compound of the formula VI is carried out by acid cyclization. Using an inorganic acid such as sulfuric or phosphoric acid or an organic acid such as methylsulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid. The process according to claim 3, characterized in that the cyclization of the compound of formula VI is carried out by basic cyclization through an unstable ester, preferably by simultaneous esterification and base addition. The process of claim 9, wherein the unstable ester is methanesulfonyl, p-toluenesulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl ester and the base is triethylamine, dimethylaniline or pyridine. Process according to claim 2, characterized in that the conversion of the group R'-NH- to cyano is carried out by diazotization followed by reaction with CN \ 12. A method according to claim 3, characterized in characterized in that the conversion of the group R @ ¹ --NH-- into cyano is performed by hydrolysis of a C. ₆ alkylcarbonylamino, R ¹ -NH-, to the corresponding amino group, where R ¹ is H, followed by diazotization and reaction with CN '. A process according to claims 1 to 12, characterized in that, before being used for cyclization in step c), the compound of formula VI is resolved into the optically active enantiomers containing the (S) -enantiomer. 14. A pharmaceutical composition having an antidepressant effect comprising citalopram produced by the process of claims 1 to 13. Intermediate of formula V for producing citalopram by the process of claim 1 -13 (V) H wherein R ¹ is H or C 1-4 alkylcarbonyl. An intermediate of formula VI for producing citalopram by the process of claim 1 H (VI) wherein R ¹ is H or C 1-4 alkylcarbonyl. and » Intermediate of formula VII for the production of citalopram by the process according to claim 1 and ₃ N " CH ₃ (VII) wherein R ¹ is H or C 1-4 alkylcarbonyl.